We report thermal to electrical energy conversion from a 150nm thick BaTiO3 film using pyroelectric cycles at 1kHz. A microfabricated platform enables temperature and electric field control with temporal resolution near 1μs. The rapid electric field changes as high as 11×105kV/cm-s, and temperature change rates as high as 6×105K/s allow exploration of pyroelectric cycles in a previously unexplored operating regime. We investigated the effect of phase difference between electric field and temperature cycles, and electric field and temperature change rates on the electrical energy generated from thermal-electrical cycles based on the pyroelectric Ericsson cycle. Complete thermodynamic cycles are possible up to the highest cycle rates tested here, and the energy density varies significantly with phase shifts between temperature and electric field waveforms. This work could facilitate the design and operation of pyroelectric cycles at high cycle rates, and aid in the design of new pyroelectric systems.

Background: Alzheimer's disease involves widespread and progressive deposition of misfolded protein tau (τ), first appearing in the entorhinal cortex, coagulating in longer polymers and insoluble fibrils. There is mounting evidence for "prion-like" trans-neuronal transmission, whereby misfolded proteins cascade along neuronal pathways, giving rise to networked spread. However, the cause-effect mechanisms by which various oligomeric τ species are produced, aggregate, and disseminate are unknown. The question of how protein aggregation and subsequent spread lead to stereotyped progression in the Alzheimer brain remains unresolved. Materials and Methods: We address these questions by using mathematically precise parsimonious modeling of these pathophysiological processes, extrapolated to the whole brain. We model three key processes: τ monomer production; aggregation into oligomers and then into tangles; and the spatiotemporal progression of misfolded τ as it ramifies into neural circuits via the brain connectome. We model monomer seeding and production at the entorhinal cortex, aggregation using Smoluchowski equations; and networked spread using our prior Network-Diffusion model. Results: This combined aggregation-network-diffusion model exhibits all hallmarks of τ progression seen in human patients. Unlike previous theoretical studies of protein aggregation, we present here an empirical validation on in vivo imaging and fluid τ measurements from large datasets. The model accurately captures not just the spatial distribution of empirical regional τ and atrophy but also patients' cerebrospinal fluid phosphorylated τ profiles as a function of disease progression. Conclusion: This unified quantitative and testable model has the potential to explain observed phenomena and serve as a test-bed for future hypothesis generation and testing in silico. Impact statement The presented aggregation-network-diffusion model exhibits all hallmarks of tau progression in human patients; it accurately captures not just the spatial distribution of empirical regional tau and atrophy but also patients' cerebrospinal fluid phosphorylated tau profiles. Thus, it serves to fill a theoretical gap between microscopic biophysical processes and empirical macroscopic measurements of pathological patterns in Alzheimer's disease. This unified quantitative and testable model has the potential to explain observed phenomena and serve as a test-bed for future hypothesis generation and testing in silico.

Solid-state pyroelectric nanomaterials can be used for thermal-to-electrical energy conversion in the presence of temperature fluctuations. This article reports investigation of energy conversion in a 200 nm thick BaTiO3 film using the pyroelectric Ericsson cycle at cycle frequencies up to 3 kHz. The high cycle frequencies were achieved due to the low thermal mass of the nanometer-scale film, unlike previous studies in which the electrical power output was limited by the rate of heat transfer through the pyroelectric material. A microfabricated platform that allowed precise thermal and electrical cycling enabled us to study the effect of electric field range, temperature oscillation amplitude, and cycle frequency on the electrical power output from pyroelectric Ericsson cycles. We measured a maximum power density of 30 W/cm3 for a temperature range 20–120°C and electric field range 100–125 kV/cm, which represents a significant improvement over past work on pyroelectric cycles. The approach presented in this article could lead to high-power waste heat harvesting in systems with high-frequency temperature oscillations.

Amyloid-beta and tau are key molecules in the pathogenesis of Alzheimer's disease, but it remains unclear how these proteins interact to promote disease. Here, by combining cross-sectional and longitudinal molecular imaging and network connectivity analyses in living humans, we identified two amyloid-beta/tau interactions associated with the onset and propagation of tau spreading. First, we show that the lateral entorhinal cortex, an early site of tau neurofibrillary tangle formation, is subject to remote, connectivity-mediated amyloid-beta/tau interactions linked to initial tau spreading. Second, we identify the inferior temporal gyrus as the region featuring the greatest local amyloid-beta/tau interactions and a connectivity profile well suited to accelerate tau propagation. Taken together, our data address long-standing questions regarding the topographical dissimilarity between early amyloid-beta and tau deposition.

Objective

To determine the independent and synergistic effects of amyloid and small vessel disease (SVD) burden on longitudinal cognitive decline in patients with subcortical vascular dementia (SVaD).

Methods

A longitudinal cohort study was conducted involving patients from outpatient clinics of 2 tertiary referral centers. Sixty-one patients with SVaD were prospectively recruited and underwent MRI, 11C-Pittsburgh compound B (PiB) PET at baseline, and a 3-year annual neuropsychological follow-up. Effects of PiB positivity and SVD markers (white matter hyperintensities [WMH], lacunes, and microbleeds) on longitudinal cognitive decline were evaluated using generalized estimation equation after controlling for age, sex, education, APOE4 allele, and follow-up interval.

Results

When individual neuropsychological tests were used as outcome measures, PiB positivity was associated with faster cognitive decline in attention, visuospatial, visual memory, and global cognition function. Higher WMH burden was associated with faster cognitive decline in attention, visuospatial, visual recognition memory, and semantic/phonemic fluency function, whereas lacunes and microbleeds had no significant effects. When global dementia rating (Clinical Dementia Rating sum of boxes) was considered as an outcome measure, however, only PiB positivity was associated with faster cognitive decline. Significant interactions between PiB positivity and higher SVD burden were found to affect cognitive decline in semantic word fluency (from WMH burden) and global dementia rating (from microbleed burden).

Conclusions

In SVaD patients, amyloid burden, independently or interactively with SVD, contributed to longitudinal cognitive decline. Amyloid deposition was the strongest poor prognostic factor.

Introduction

Differential patterns of brain atrophy on structural magnetic resonance imaging (MRI) revealed four reproducible subtypes of Alzheimer's disease (AD): (1) "typical", (2) "limbic-predominant", (3) "hippocampal-sparing", and (4) "mild atrophy". We examined the neurobiological characteristics and clinical progression of these atrophy-defined subtypes.

Methods

The four subtypes were replicated using a clustering method on MRI data in 260 amyloid-β-positive patients with mild cognitive impairment or AD dementia, and we subsequently tested whether the subtypes differed on [¹⁸ F]flortaucipir (tau) positron emission tomography, white matter hyperintensity burden, and rate of global cognitive decline.

Results

Voxel-wise and region-of-interest analyses revealed the greatest neocortical tau load in hippocampal-sparing (frontoparietal-predominant) and typical (temporal-predominant) patients, while limbic-predominant patients showed particularly high entorhinal tau. Typical patients with AD had the most pronounced white matter hyperintensity load, and hippocampal-sparing patients showed the most rapid global cognitive decline.

Discussion

Our data suggest that structural MRI can be used to identify biologically and clinically meaningful subtypes of AD.

Background

We investigated the independent effects of Alzheimer's disease (AD) and cerebrovascular disease (CVD) pathologies on brain structural changes and cognition.

Methods

Amyloid burden (Pittsburgh compound B [PiB] retention ratio), CVD markers (volume of white matter hyperintensities [WMH] and number of lacunae), and structural changes (cortical thickness and hippocampal shape) were measured in 251 cognitively impaired patients. Path analyses were utilized to assess the effects of these markers on cognition.

Results

PiB retention ratio was associated with hippocampal atrophy, which was associated with memory impairment. WMH were associated with frontal thinning, which was associated with executive and memory dysfunctions. PiB retention ratio and lacunae were also associated with memory and executive dysfunction without the mediation of hippocampal or frontal atrophy.

Conclusions

Our results suggest that the impacts of AD and CVD pathologies on cognition are mediated by specific brain regions.

Background

We tested our hypothesis that the white matter network might mediate the effect of amyloid and small vessel disease (SVD) on cortical thickness and/or cognition.

Methods

We prospectively recruited 232 patients with cognitive impairment. Amyloid was assessed using Pittsburgh compound B-PET. SVD was quantified as white matter hyperintensity volume and lacune number. The regional white matter network connectivity was measured as regional nodal efficiency by applying graph theoretical analysis to diffusion tensor imaging data. We measured cortical thickness and performed neuropsychological tests.

Results

SVD burden was associated with decreased nodal efficiency in the bilateral frontal, lateral temporal, lateral parietal, and occipital regions. Path analyses showed that the frontal nodal efficiency mediated the effect of SVD on the frontal atrophy and frontal-executive dysfunction. The temporoparietal nodal efficiency mediated the effect of SVD on the temporoparietal atrophy and memory dysfunction. However, Pittsburgh compound B retention ratio affected cortical atrophy and cognitive impairment without being mediated by nodal efficiency.

Conclusions

We suggest that a disrupted white matter network mediates the effect of SVD, but not amyloid, on specific patterns of cortical atrophy and/or cognitive impairment. Therefore, our findings provide insight to better understand how amyloid and SVD burden can give rise to brain atrophy or cognitive impairment in specific patterns.

Importance

Better understanding is needed of the degree to which individuals tolerate Alzheimer disease (AD)-like pathological tau with respect to brain structure (brain resilience) and cognition (cognitive resilience).

Objective

To examine the demographic (age, sex, and educational level), genetic (APOE-ε4 status), and neuroimaging (white matter hyperintensities and cortical thickness) factors associated with interindividual differences in brain and cognitive resilience to tau positron emission tomography (PET) load and to changes in global cognition over time.

Design, setting, an participants

In this cross-sectional, longitudinal study, tau PET was performed from June 1, 2014, to November 30, 2017, and global cognition monitored for a mean [SD] interval of 2.0 [1.8] years at 3 dementia centers in South Korea, Sweden, and the United States. The study included amyloid-β-positive participants with mild cognitive impairment or AD dementia. Data analysis was performed from October 26, 2018, to December 11, 2019.

Exposures

Standard dementia screening, cognitive testing, brain magnetic resonance imaging, amyloid-β PET and cerebrospinal fluid analysis, and flortaucipir (tau) labeled with fluor-18 (18F) PET.

Main outcomes and measures

Separate linear regression models were performed between whole cortex [18F]flortaucipir uptake and cortical thickness, and standardized residuals were used to obtain a measure of brain resilience. The same procedure was performed for whole cortex [18F]flortaucipir uptake vs Mini-Mental State Examination (MMSE) as a measure of cognitive resilience. Bivariate and multivariable linear regression models were conducted with age, sex, educational level, APOE-ε4 status, white matter hyperintensity volumes, and cortical thickness as independent variables and brain and cognitive resilience measures as dependent variables. Linear mixed models were performed to examine whether changes in MMSE scores over time differed as a function of a combined brain and cognitive resilience variable.

Results

A total of 260 participants (145 [55.8%] female; mean [SD] age, 69.2 [9.5] years; mean [SD] MMSE score, 21.9 [5.5]) were included in the study. In multivariable models, women (standardized β = -0.15, P = .02) and young patients (standardized β = -0.20, P = .006) had greater brain resilience to pathological tau. Higher educational level (standardized β = 0.23, P < .001) and global cortical thickness (standardized β = 0.23, P < .001) were associated with greater cognitive resilience to pathological tau. Linear mixed models indicated a significant interaction of brain resilience × cognitive resilience × time on MMSE (β [SE] = -0.235 [0.111], P = .03), with steepest slopes for individuals with both low brain and cognitive resilience.

Conclusions and relevance

Results of this study suggest that women and young patients with AD have relative preservation of brain structure when exposed to neocortical pathological tau. Interindividual differences in resilience to pathological tau may be important to disease progression because participants with both low brain and cognitive resilience had the most rapid cognitive decline over time.

Background

THK5351 and flortaucipir tau ligands have high affinity for paired helical filament tau, yet diverse off-target bindings have been reported. Recent data support the hypothesis that THK5351 binds to monoamine oxidase B (MAO-B) expressed from reactive astrocytes and that flortaucipir has an affinity toward MAO-A and B; however, pathological evidence is lacking. We performed a head-to-head comparison of the two tau ligands in a sporadic Creutzfeldt-Jakob disease (CJD) patient and performed an imaging-pathological correlation study.

Case presentation

A 67-year-old man visited our clinic a history of 6 months of rapidly progressive dementia, visual disturbance, and akinetic mutism. Diffusion-weighted imaging showed cortical diffusion restrictions in the left temporo-parieto-occipital regions. ¹⁸F-THK5351 PET, but not ¹⁸F-flortaucipir PET showed high uptake in the left temporo-parieto-occipital regions, largely overlapping with the diffusion restricted areas. Cerebrospinal fluid analysis was weakly positive for 14-3-3 protein and pathogenic prion protein was found. The patient showed rapid cognitive decline along with myoclonic seizures and died 13 months after his first visit. A post-mortem study revealed immunoreactivity for PrP^sc, no evidence of neurofibrillary tangles, and abundant astrocytosis which was reactive for MAO-B antibody.

Conclusions

Our findings add pathological evidence that increased THK5351 uptake in sporadic CJD patients might be caused by an off-target binding driven by its high affinity for MAO-B.